3,4- Methylenedioxymethamphetamine (MDMA), "Ecstasy", is a highly abused amphetamine analog growing in popularity worldwide. Neurotoxic effects of MDMA are characterized by decreases in serotonin (5HT) tissue content and tryptophan hydroxylase (TPH) activity, and loss of 5HT transporters. MDMAinduced acute changes in electron transport chain (ETC) activity and reactive species formation underlie our hypothesis linking acute and toxic effects of MDMA. Complex I/Ill, ll/lll and IV of the ETC are acutely decreased following MDMA. Additionally, nitric oxide (NO) acutely increases, and blocking its synthesis protects against serotonergic depletions. These acute effects of MDMA administration can alter the balance of bioenergetic and oxidative processes in the brain. We hypothesize that one effect of this imbalance is aggregation of damaged protein. The overall objectives of this proposal are: 1) Examine the relationship between MDMA-induced NO production and ETC activity, 2) Explore MDMA-induced protein aggregation in serotonergic specific degredation. The overarching hypothesis is that acute decreases in ETC and proteosomal function mediated by NO lead to specific serotonergic degredation.